Renal Unit, UCL Great Ormond Street Hospital for Children NHS Foundation Trust and Institute of Child Health, London, UK.
Radiology Department, UCL Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
J Bone Miner Res. 2021 Jan;36(1):133-142. doi: 10.1002/jbmr.4158. Epub 2020 Sep 11.
Serum calcium (Ca), bone biomarkers, and radiological imaging do not allow accurate evaluation of bone mineral balance (BMB), a key determinant of bone mineral density (BMD) and fracture risk. We studied naturally occurring stable (non-radioactive) Ca isotopes in different body pools as a potential biomarker of BMB. Ca and Ca are absorbed from our diet and sequestered into different body compartments following kinetic principles of isotope fractionation; isotopically light Ca is preferentially incorporated into bone, whereas heavier Ca preferentially remains in blood and is excreted in urine and feces. Their ratio (δ Ca) in serum and urine increases during bone formation and decreases with bone resorption. In 117 healthy participants, we measured Ca isotopes, biomarkers, and BMD by dual-energy X-ray absorptiometry (DXA) and tibial peripheral quantitative CT (pQCT). Ca and Ca were measured by multi-collector ionization-coupled plasma mass-spectrometry in serum, urine, and feces. The relationship between bone Ca gain and loss was calculated using a compartment model. δ Ca and δ Ca were higher in children (n = 66, median age 13 years) compared with adults (n = 51, median age 28 years; p < 0.0001 and p = 0.008, respectively). δ Ca increased with height in boys (p < 0.001, R = 0.65) and was greatest at Tanner stage 4. δ Ca correlated positively with biomarkers of bone formation (25-hydroxyvitaminD [p < 0.0001, R = 0.37] and alkaline phosphatase [p = 0.009, R = 0.18]) and negatively with bone resorption marker parathyroid hormone (PTH; p = 0.03, R = 0.13). δ Ca strongly positively correlated with tibial cortical BMD Z-score (n = 62; p < 0.001, R = 0.39) but not DXA. Independent predictors of tibial cortical BMD Z-score were δ Ca (p = 0.004, β = 0.37), 25-hydroxyvitaminD (p = 0.04, β = 0.19) and PTH (p = 0.03, β = -0.13), together predicting 76% of variability. In conclusion, naturally occurring Ca isotope ratios in different body compartments may provide a novel, non-invasive method of assessing bone mineralization. Defining an accurate biomarker of BMB could form the basis of future studies investigating Ca dynamics in disease states and the impact of treatments that affect bone homeostasis. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
血清钙（Ca）、骨生物标志物和影像学检查均无法准确评估骨矿物质平衡（BMB），而 BMB 是骨矿物质密度（BMD）和骨折风险的关键决定因素。我们研究了不同身体池中天然存在的稳定（非放射性）Ca 同位素，将其作为 BMB 的潜在生物标志物。Ca 和 Ca 从我们的饮食中吸收，并根据同位素分馏的动力学原理被隔离到不同的身体隔室中；同位素较轻的 Ca 优先掺入骨骼，而较重的 Ca 则优先留在血液中，并通过尿液和粪便排泄。它们在血清和尿液中的比值（δ Ca）在骨形成过程中增加，在骨吸收过程中减少。在 117 名健康参与者中，我们通过双能 X 射线吸收法（DXA）和胫骨外周定量 CT（pQCT）测量了 Ca 同位素、生物标志物和 BMD。通过多收集器离子耦合等离子体质谱法在血清、尿液和粪便中测量 Ca 和 Ca。使用隔室模型计算骨 Ca 获得和损失之间的关系。δ Ca 和 δ Ca 在儿童（n = 66，中位年龄 13 岁）中高于成人（n = 51，中位年龄 28 岁；p < 0.0001 和 p = 0.008，分别）。δ Ca 在男孩中随身高增加（p < 0.001，R = 0.65），在 Tanner 分期 4 时最大。δ Ca 与骨形成生物标志物（25-羟维生素 D [p < 0.0001，R = 0.37]和碱性磷酸酶 [p = 0.009，R = 0.18]）呈正相关，与骨吸收标志物甲状旁腺激素（PTH；p = 0.03，R = 0.13）呈负相关。δ Ca 与胫骨皮质 BMD Z 评分呈强烈正相关（n = 62；p < 0.001，R = 0.39），但与 DXA 无关。胫骨皮质 BMD Z 评分的独立预测因子是 δ Ca（p = 0.004，β = 0.37）、25-羟维生素 D（p = 0.04，β = 0.19）和 PTH（p = 0.03，β = -0.13），共同预测了 76%的变异性。总之，不同身体隔室中天然存在的 Ca 同位素比值可能提供一种评估骨矿化的新的非侵入性方法。定义 BMB 的准确生物标志物可以为未来研究疾病状态下的 Ca 动力学以及影响骨内稳态的治疗方法奠定基础。
